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1.
Phys Rev Lett ; 127(9): 098101, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34506203

RESUMO

Cardiac fibrosis is a well-known arrhythmogenic condition which can lead to sudden cardiac death. Physically, fibrosis can be viewed as a large number of small obstacles in an excitable medium, which may create nonlinear wave turbulence or reentry. The relation between the specific texture of fibrosis and the onset of reentry is of great theoretical and practical importance. Here, we present a conceptual framework which combines functional aspects of propagation manifested as conduction blocks, with reentry wavelength and geometrical clusters of fibrosis. We formulate them into the single concept of minimal functional cluster and through extensive simulations show that it characterizes the path of reexcitation accurately, and importantly its size distribution quantitatively predicts the reentry probability for different fibrosis densities and tissue excitabilities.


Assuntos
Sistema de Condução Cardíaco/fisiopatologia , Modelos Cardiovasculares , Miocárdio/patologia , Potenciais de Ação , Análise por Conglomerados , Fibrose/patologia , Fibrose/fisiopatologia , Humanos , Dinâmica não Linear
2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445632

RESUMO

Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-ß1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-ß1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses fibrosis and mediators of the TGF-ß1 pathway in the bleomycin (BLM) model of fibrosis. Fibrosis was induced into the skin of female C57BL/6 mice by repeated injections of BLM (50 µg/100 µL) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)2pD using 5, 15, or 30 µg/kg for 21 days. The injected skin was biopsied; analyzed histologically; examined for total collagen by Sircol; and examined for mRNA expression of MMP-13, BMP-7, MCP-1, Gli1, and Gli2 by TR-PCR. Spleen was analyzed for lymphocytes using flow cytometry. Serum was analyzed for cytokines using a multiplexed ELISA. Results showed that all three doses of 17,20S(OH)2pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)2pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-α, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)2pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)2pD offers new therapeutic approaches for fibrotic disorders.


Assuntos
Bleomicina/toxicidade , Colecalciferol/análogos & derivados , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Escleroderma Sistêmico/complicações , Dermatopatias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/toxicidade , Colecalciferol/farmacologia , Citocinas/metabolismo , Feminino , Fibrose/etiologia , Fibrose/patologia , Camundongos , Camundongos Endogâmicos C57BL , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/patologia , Dermatopatias/etiologia , Dermatopatias/patologia
3.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445567

RESUMO

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Fibrose/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Animais , Fibrose/metabolismo , Fibrose/patologia , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Receptores de Lisoesfingolipídeo
4.
FASEB J ; 35(9): e21861, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416029

RESUMO

Duchenne muscular dystrophy (DMD) is an intractable genetic disease associated with progressive skeletal muscle weakness and degeneration. Recently, it was reported that intraperitoneal injections of ketone bodies partially ameliorated muscular dystrophy by increasing satellite cell (SC) proliferation. Here, we evaluated whether a ketogenic diet (KD) with medium-chain triglycerides (MCT-KD) could alter genetically mutated DMD in model rats. We found that the MCT-KD significantly increased muscle strength and fiber diameter in these rats. The MCT-KD significantly suppressed the key features of DMD, namely, muscle necrosis, inflammation, and subsequent fibrosis. Immunocytochemical analysis revealed that the MCT-KD promoted the proliferation of muscle SCs, suggesting enhanced muscle regeneration. The muscle strength of DMD model rats fed with MCT-KD was significantly improved even at the age of 9 months. Our findings suggested that the MCT-KD ameliorates muscular dystrophy by inhibiting myonecrosis and promoting the proliferation of muscle SCs. As far as we can ascertain, this is the first study to apply a functional diet as therapy for DMD in experimental animals. Further studies are needed to elucidate the underlying mechanisms of the MCT-KD-induced improvement of DMD.


Assuntos
Dieta Cetogênica , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Distrofia Muscular de Duchenne/dietoterapia , Distrofia Muscular de Duchenne/fisiopatologia , Triglicerídeos/química , Triglicerídeos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose/dietoterapia , Fibrose/patologia , Inflamação/dietoterapia , Inflamação/patologia , Cetonas/sangue , Cetose , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Necrose/dietoterapia , Necrose/patologia , Ratos , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Triglicerídeos/uso terapêutico
5.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361060

RESUMO

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.


Assuntos
Sistema Nervoso Central/patologia , Fibrose/patologia , Miocárdio/patologia , Neurônios/patologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Sistema Nervoso Central/metabolismo , Feminino , Fibrose/metabolismo , Proteínas HMGA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Neurônios/metabolismo , Fenótipo , Fosforilação
6.
Immunity ; 54(7): 1374-1376, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34260885

RESUMO

In a recent issue of Nature, Hoeffel et al. describe a novel pathway of sterile tissue repair utilizing a mouse model of sunburn. This wound healing pathway is coordinated by sensory neuron-derived TAFA4 that induces IL-10 production from Tim4+ dermal macrophages to prevent sustained inflammation and the emergence of tissue fibrosis.


Assuntos
Células Receptoras Sensoriais/patologia , Queimadura Solar/patologia , Cicatrização/fisiologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose/metabolismo , Fibrose/patologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Transdução de Sinais/fisiologia , Pele/metabolismo , Pele/patologia , Queimadura Solar/metabolismo
7.
Methods Mol Biol ; 2350: 313-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34331294

RESUMO

We describe a multiplexed imaging mass spectrometry approach especially suitable for fibrosis research. Fibrosis is a process characterized by excessive extracellular matrix (ECM) secretion. Buildup of ECM impairs tissue and organ function to promote further progression of disease. It is an ongoing analytical challenge to access ECM for diagnosis and therapeutic treatment of fibrosis. Recently, we reported the use of the enzyme collagenase type III to target the ECM proteome in thin histological tissue sections of fibrotic diseases including hepatocellular carcinoma, breast cancer, prostate cancer, lung cancer and aortic valve stenosis. Detection of collagenase type III peptides by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) allows localization of ECM peptide sequences to specific regions of fibrosis. We have further identified that the ECM proteome accessed by collagenase type III has on average 3.7 sites per protein that may be differentially N-glycosylated. N-glycosylation is a major posttranslational modification of the ECM proteome, influencing protein folding, secretion, and organization. Understanding both N-glycosylation signaling and regulation of ECM expression significantly informs on ECM signaling in fibrosis.


Assuntos
Biomarcadores , Matriz Extracelular/metabolismo , Histocitoquímica/métodos , Espectrometria de Massas/métodos , Polissacarídeos/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Glicosilação , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica/métodos , Peptídeos/metabolismo , Processamento de Proteína Pós-Traducional , Proteômica/métodos , Pesquisa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Fluxo de Trabalho
8.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299192

RESUMO

Transforming growth factor-ß (TGF-ß) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor microenvironment (TME) for accelerating invasion, metastasis, angiogenesis, and immunosuppression. Increasing evidence suggest a pleiotropic nature of TGF-ß signaling as a critical pathway for generating fibrotic TME, which contains numerous cancer-associated fibroblasts (CAFs), extracellular matrix proteins, and remodeling enzymes. Its pathogenic roles and working mechanisms in tumorigenesis are still largely unclear. Importantly, recent studies successfully demonstrated the clinical implications of fibrotic TME in cancer. This review systematically summarized the latest updates and discoveries of TGF-ß signaling in the fibrotic TME.


Assuntos
Fibroblastos Associados a Câncer/patologia , Fibrose/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibrose/metabolismo , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neovascularização Patológica/patologia , Transdução de Sinais , Microambiente Tumoral
9.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299270

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defined. Under the definition of HFpEF there is a wide spectrum of different myocardial structural alterations. Myocardial hypertrophy and fibrosis, coronary microvascular dysfunction, oxidative stress and inflammation are only some of the main pathological detectable processes. Furthermore, there is a lack of effective pharmacological targets to improve HFpEF patients' outcomes and risk factors control is the primary and unique approach to treat those patients. Myocardial tissue characterization, through invasive and non-invasive techniques, such as endomyocardial biopsy and cardiac magnetic resonance respectively, may represent the starting point to understand the genetic, molecular and pathophysiological mechanisms underlying this complex syndrome. The correlation between histopathological findings and imaging aspects may be the future challenge for the earlier and large-scale HFpEF diagnosis, in order to plan a specific and effective treatment able to modify the disease's natural course.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Miocárdio/patologia , Volume Sistólico/fisiologia , Ensaios Clínicos como Assunto , Fibrose/metabolismo , Fibrose/patologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Espectroscopia de Ressonância Magnética , Miocárdio/metabolismo
10.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299227

RESUMO

Our previous study showed that in adult mice, conditional Nedd4-2-deficiency in club and alveolar epithelial type II (AE2) cells results in impaired mucociliary clearance, accumulation of Muc5b and progressive, terminal pulmonary fibrosis within 16 weeks. In the present study, we investigated ultrastructural alterations of the alveolar epithelium in relation to interstitial remodeling in alveolar septa as a function of disease progression. Two, eight and twelve weeks after induction of Nedd4-2 knockout, lungs were fixed and subjected to design-based stereological investigation at the light and electron microscopic level. Quantitative data did not show any abnormalities until 8 weeks compared to controls. At 12 weeks, however, volume of septal wall tissue increased while volume of acinar airspace and alveolar surface area significantly decreased. Volume and surface area of alveolar epithelial type I cells were reduced, which could not be compensated by a corresponding increase of AE2 cells. The volume of collagen fibrils in septal walls increased and was linked with an increase in blood-gas barrier thickness. A high correlation between parameters reflecting interstitial remodeling and abnormal AE2 cell ultrastructure could be established. Taken together, abnormal regeneration of the alveolar epithelium is correlated with interstitial septal wall remodeling.


Assuntos
Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/ultraestrutura , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Remodelação das Vias Aéreas/fisiologia , Células Epiteliais Alveolares/fisiologia , Animais , Células Epiteliais/metabolismo , Feminino , Fibrose/metabolismo , Fibrose/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Ubiquitina-Proteína Ligases Nedd4/genética , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Surfactantes Pulmonares , Mucosa Respiratória/metabolismo
11.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203824

RESUMO

In drug discovery, often animal models are used that mimic human diseases as closely as possible. These animal models can be used to address various scientific questions, such as testing and evaluation of new drugs, as well as understanding the pathogenesis of diseases. Currently, the most commonly used animal models in the field of fibrosis are rodents. Unfortunately, rodent models of fibrotic disease are costly and time-consuming to generate. In addition, present models are not very suitable for screening large compounds libraries. To overcome these limitations, there is a need for new in vivo models. Zebrafish has become an attractive animal model for preclinical studies. An expanding number of zebrafish models of human disease have been documented, for both acute and chronic diseases. A deeper understanding of the occurrence of fibrosis in zebrafish will contribute to the development of new and potentially improved animal models for drug discovery. These zebrafish models of fibrotic disease include, among others, cardiovascular disease models, liver disease models (categorized into Alcoholic Liver Diseases (ALD) and Non-Alcoholic Liver Disease (NALD)), and chronic pancreatitis models. In this review, we give a comprehensive overview of the usage of zebrafish models in fibrotic disease studies, highlighting their potential for high-throughput drug discovery and current technical challenges.


Assuntos
Modelos Animais de Doenças , Fibrose/patologia , Peixe-Zebra/fisiologia , Animais , Fibrose/genética
12.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298917

RESUMO

Musculoskeletal conditions are known to involve biological, psychological, social and, often, lifestyle elements. However, these domains are generally considered in isolation from each other. This siloed approach is unlikely to be adequate to understand the complexity of these conditions and likely explains a major component of the disappointing effects of treatment. This paper presents a hypothesis that aims to provide a foundation to understand the interaction and integration between these domains. We propose a hypothesis that provides a plausible link between psychology and lifestyle factors with tissue level effects (such as connective tissue dysregulation/accumulation) in musculoskeletal conditions that is founded on understanding the molecular basis for interaction between systemic and local inflammation. The hypothesis provides plausible and testable links between mind and body, for which empirical evidence can be found for many aspects. We present this hypothesis from the perspective of connective tissue biology and pathology (fibrosis), the role of inflammation locally (tissue level), and how this inflammation is shaped by systemic inflammation through bidirectional pathways, and various psychological and lifestyle factors via their influence on systemic inflammation. This hypothesis provides a foundation for new consideration of the development and refinement of personalized multidimensional treatments for individuals with musculoskeletal conditions.


Assuntos
Tecido Conjuntivo/patologia , Inflamação/patologia , Doenças Musculoesqueléticas/patologia , Animais , Fibrose/patologia , Humanos , Estilo de Vida
13.
Front Immunol ; 12: 639260, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093526

RESUMO

The parasitic nematode Trichinella spiralis causes trichinellosis, a serious food-borne parasitic zoonosis worldwide. Infection with T. spiralis may also cause myocarditis. In the present study, we used mouse models to assess the impact of blockage of galectin-receptor interactions by α-lactose on cardiac immunopathology during acute T. spiralis experimental infection. Our data demonstrated that, after T. spiralis infection, blockage of galectin-receptor interactions resulted in cardiac dysfunction detected by transthoracic conventional echocardiography, and increased serum Gal-3 level, a biomarker of myocardial damage. In addition, there were increased eosinophil number in peripheral blood, and increased eosinophil infiltration in the heart and spleen tissues accompanied with increased mRNA levels of eosinophil granule proteins (including eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO)) and IL-5 in these organs; increased cardiac fibrosis accompanied with increased Gal-3 and collagen 1 expressions in the hearts of mice with blockage of galectin-receptor interactions after T. spiralis infection. Correlation analysis showed that significant positive correlations existed between the mRNA levels of Gal-3 and ECP/EPO/eosinophil major basic protein/IL-5/CCL11/CCR3/α-SMA/collagen 1 in the hearts of both T. spiralis-infected mice and T. spiralis-infected mice with blockage of galectin-receptor interactions. Our data suggest that galectin-receptor interactions play a pivotal role during acute T. spiralis infection, and lack of galectin-receptor interactions upregulates Gal-3 which, in turn, leads to elevated heart eosinophil recruitment, exacerbated heart pathology and fibrosis, and heart functional damage.


Assuntos
Galectinas/metabolismo , Cardiopatias/metabolismo , Cardiopatias/patologia , Coração/parasitologia , Trichinella spiralis/parasitologia , Triquinelose/metabolismo , Triquinelose/patologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinofilia/metabolismo , Eosinofilia/parasitologia , Eosinofilia/patologia , Eosinófilos/metabolismo , Eosinófilos/parasitologia , Eosinófilos/patologia , Feminino , Fibrose/metabolismo , Fibrose/parasitologia , Fibrose/patologia , Cardiopatias/parasitologia , Camundongos , RNA Mensageiro/metabolismo , Baço/metabolismo , Baço/parasitologia , Baço/patologia , Triquinelose/parasitologia , Regulação para Cima/fisiologia
14.
Chembiochem ; 22(15): 2516-2520, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34132013

RESUMO

The outbreak of SARS-CoV-2 has been an extraordinary event that constituted a global health emergency. As the novel coronavirus is continuing to spread over the world, the need for therapeutic agents to control this pandemic is increasing. αV ß6 Integrin may be an intriguing target not only for the inhibition of SARS-CoV-2 entry, but also for the diagnosis/treatment of COVID-19 related fibrosis, an emerging type of fibrotic disease which will probably affect a significant part of the recovered patients. In this short article, the possible role of this integrin for fighting COVID-19 is discussed on the basis of recently published evidence, showing how its underestimated involvement may be interesting for the development of novel pharmacological tools.


Assuntos
COVID-19/virologia , Fibrose/virologia , Cadeias beta de Integrinas/metabolismo , SARS-CoV-2/isolamento & purificação , COVID-19/metabolismo , COVID-19/patologia , Fibrose/metabolismo , Fibrose/patologia , Humanos
15.
FASEB J ; 35(7): e21497, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34152015

RESUMO

Despite the increasing understanding of the pathophysiology of hepatic fibrosis, the therapies to combat it remain inadequate. Fluorofenidone (AKF-PD) is a novel pyridone agent able to ameliorate hepatic fibrosis in an experimental hepatic fibrosis model induced by dimethylnitrosamine. However, the underlying mechanism remains to be further elucidated. In light of the critical role of the NF-κB pathway in inflammation and hepatic fibrosis, together with the preliminary finding that AKF-PD decreases the release of proinflammatory cytokines in the endotoxemia and unilateral ureteral occlusion model, the aim of this study was to explore whether AKF-PD exerts an antifibrotic effect in hepatic fibrosis by inhibiting inflammation and suppressing the activation of the NF-κB pathway in vivo and in vitro. To test this possibility, the effect of AKF-PD on hepatic fibrosis models induced by both carbon tetrachloride (CCL4 ) and porcine serum (PS) was investigated. Our results showed that AKF-PD treatment ameliorated hepatic injury and fibrosis in both models. Furthermore, the administration of AKF-PD induced a robust anti-inflammatory reaction revealed by the downregulation of the proinflammatory cytokines as well as the suppression of the infiltration of inflammatory cells in the fibrotic liver. The analysis of the mechanism of action demonstrated that the attenuation of the production of proinflammatory cytokines and chemokines mediated by AKF-PD in vivo and in vitro were accompanied by the suppression in the activation of the NF-κB signaling pathway. In conclusion, AKF-PD might be considered as an antifibrotic agent attenuating hepatic inflammation and fibrosis potentially through the suppression of the NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Hepatopatias/prevenção & controle , NF-kappa B/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Piridonas/farmacologia , Animais , Células Cultivadas , Fibrose/metabolismo , Fibrose/patologia , Inflamação/metabolismo , Inflamação/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Ratos , Ratos Sprague-Dawley
16.
J Food Sci ; 86(7): 3265-3276, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34160066

RESUMO

Hyperuricemia contributes to chronic kidney disease development. However, it has been historically viewed with limited research interest. In this study, we mimicked the development of hyperuricemic nephropathy by using a potassium oxonate-induced hyperuricemia rat model. We found that administering vitamin C at 10 mg/kg/day effectively ameliorated hyperuricemic nephropathy. Compared to the control group, rats with hyperuricemia had significantly increased serum uric acid level, xanthine oxidase activity, and urine microalbumin level, by 5-fold, 1.5-fold, and 4-fold, respectively. At the same time, vitamin C supplementation reverted these values by 20% for serum uric acid level and xanthine oxidase activity and 50% for microalbumin level. Vitamin C also alleviated renal pathology and decreased the expression of pro-inflammatory and pro-fibrotic markers. A further mechanistic study suggested that vitamin C might attenuate hyperuricemic nephropathy in renal tubular epithelial cells induced by monosodium urate (MSU) crystal, at least in part, by directly inhibiting IL-6/JAK2/STAT3 signaling pathway. Meanwhile, in macrophages, vitamin C inhibited the expression of TGF-ß, and reduced ROS level induced by MSU by about 35%. In short, our results suggest that vitamin C supplementation delay the progression of hyperuricemic nephropathy.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Fibrose/prevenção & controle , Hiperuricemia/tratamento farmacológico , Inflamação/prevenção & controle , Nefropatias/tratamento farmacológico , Animais , Fibrose/etiologia , Fibrose/patologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Hiperuricemia/patologia , Inflamação/etiologia , Inflamação/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ácido Oxônico/toxicidade , Ratos , Ratos Sprague-Dawley
17.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068941

RESUMO

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Fibrose/prevenção & controle , Lisina/química , Nitrofuranos/farmacologia , Ramipril/farmacologia , Sulfonas/farmacologia , Ubiquitinação , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Quimioterapia Combinada , Feminino , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Camundongos , Camundongos Endogâmicos DBA
18.
Am J Physiol Heart Circ Physiol ; 320(6): H2416-H2428, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33989083

RESUMO

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. We characterized eNOS null and wild-type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, eight groups of mice were divided into four groups of eNOS null mice and WT mice; half of the mice received angiotensin II (ANG II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, ANG II administration not only increased cardiac fibrosis but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.NEW & NOTEWORTHY ECs compensate for eNOS deficiency by increasing the secretion of NRG1. NRG1 administration prevents cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. NRG1 expression is regulated by miR-134.


Assuntos
Células Endoteliais/metabolismo , Frequência Cardíaca/genética , Coração/efeitos dos fármacos , MicroRNAs/metabolismo , Miocárdio/patologia , Neuregulina-1/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/metabolismo , Angiotensina II/farmacologia , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Diástole/efeitos dos fármacos , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica , Frequência Cardíaca/efeitos dos fármacos , Rim/patologia , Camundongos , Camundongos Knockout , Neuregulina-1/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Distribuição Aleatória , Vasoconstritores/farmacologia
20.
Nature ; 594(7861): 94-99, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34012116

RESUMO

Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair1, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors-a subset of GINIP+ neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4-IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.


Assuntos
Citocinas/metabolismo , Macrófagos/metabolismo , Regeneração , Células Receptoras Sensoriais/metabolismo , Cicatrização , Animais , Sobrevivência Celular , Citocinas/deficiência , Modelos Animais de Doenças , Feminino , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Interleucina-10/biossíntese , Interleucina-10/metabolismo , Macrófagos/efeitos da radiação , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Receptoras Sensoriais/efeitos da radiação , Pele/patologia , Pele/efeitos da radiação , Queimadura Solar/complicações , Queimadura Solar/etiologia , Queimadura Solar/metabolismo , Queimadura Solar/patologia , Raios Ultravioleta/efeitos adversos
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